Manganese dioxide nanoparticles attenuate pathological retinal angiogenesis by inhibiting the PLK1/AKT/FOXO1 signaling axis

Abstract Pathological retinal neovascularization (RNV) is a primary etiology of irreversible vision loss in debilitating conditions such as diabetic retinopathy and retinal vein occlusion. While metal-oxide nanomaterials have emerged as potent candidates for anti-angiogenic intervention, their clinical translation remains constrained by persistent biosafety concerns and inherent cytotoxicity. Manganese dioxide nanoparticles (MnO 2 NPs), distinguished by their robust enzyme-mimetic activity and microenvironment-responsive properties, have demonstrated substantial therapeutic promise in oncology; however, their specific function and underlying mechanisms in RNV remain largely uncharacterized. This study provides a systematic investigation into the anti-angiogenic potential of MnO 2 NPs and identifies molecular pathways that may underlie their activity, representing a step toward mechanistic proof-of-concept. Our results demonstrate that MnO 2 NPs possess exceptional biocompatibility both in vitro and in vivo . These nanoparticles exert a potent, dose-dependent inhibitory effect on the proliferation, migration, and sprouting of human umbilical vein endothelial cells (HUVECs). Moving to in vivo validation, MnO 2 NPs demonstrate a distinct capacity to modulate physiological retinal vascular development in neonatal mice and, more critically, markedly attenuate pathological neovascularization in an oxygen-induced retinopathy model. Mechanistically, integrated transcriptomic analysis revealed a significant modulation of angiogenesis-related gene clusters, which—along with Western blot validation—confirmed that MnO 2 NPs exert their effects by targeting the PLK1/AKT/FOXO1 signaling axis. In conclusion, MnO 2 NPs emerge as a compelling and innovative therapeutic candidate for managing vision-threatening ocular vascular disorders. These findings not only offer a targeted pharmacological intervention for retinal diseases but also provide a mechanistic blueprint for the rational design of next-generation multifunctional nanomedicines.